Ghrelin is a physiologically active substance consisting of 28 amino acids, and is mainly produced in the stomach. Ghrelin includes active type (acyl form) and inactive type (des-acyl form), and the active type is produced by the addition, by GOAT, of fatty acid to the serine residue at the 3-position of ghrelin [non-patent document 1]. The fatty acid to be added to ghrelin by GOAT includes octanoic acid, decanoylic acid and the like. The target of the active type ghrelin is mainly a growth hormone secretagogue receptor (GHSR) in the stomach, and the activation of signal causes promoted food ingestion and low energy consumption. Therefore, GOAT plays a key role in the control of food ingestion and energy metabolism.
The decrease of active type ghrelin due to the inhibition of GOAT leads to a promoted energy consumption [non-patent document 2] and promoted utilization of lipid as an energy source thereof. Promotion of such systemically lipid utilization brings about lower fat content of adipose tissues, and further, decreased weight of adipose tissues [non-patent document 3]. That is, since a GOAT inhibitor acts on an environment, which permits increase of obesity formation factors such as excess fat ingestion, in the direction toward suppression thereof, it can be used as an antiobesity drug for the treatment of obesity. Furthermore, since ghrelin increases along with a weight loss therapy of obese patients, a GOAT inhibitor provides a further antiobesity effect as a medicament that decreases ghrelin [non-patent document 4]. In addition, promoted utilization of lipid is also expected to improve lipid abnormality. Moreover, since it may also have a sugar metabolism improving effect [non-patent document 5], a GOAT inhibitor is expected to be effective for the prophylaxis or suppression of metabolic disorders including metabolic syndrome.
GOAT inhibition increases des-acyl ghrelin in the inactive type. This has also been confirmed in genetically-altered animals wherein GOAT has been knocked out [non-patent document 6]. Since des-acyl ghrelin suppresses activation of microglia by β-amyloid, it is expected to be a therapeutic drug for Alzheimer's disease [non-patent document 7]. Furthermore, since des-acyl ghrelin suppresses nerve cell death due to low oxygen and low glucose, it is expected to be a therapeutic drug for ischemic cerebral dysfunctions such as cerebrovascular dementia, cerebral apoplexy, cerebral infarction and the like and neurodegenerative diseases such as Parkinson's disease and the like [non-patent document 8]. In addition, a heart protecting action including suppression of ischemic cardiac diseases and cardiac hypertrophy is also expected [non-patent document 9]. Therefore, the compound of the present invention has a potential of a therapeutic drug for a metabolic disease with a heart protecting action.
Ghrelin is also involved in the preference control mechanism, and activates consumption of rewarding substances (alcohol, sweetener, narcotic etc.) [non-patent document 10]. Therefore, decrease of ghrelin by inhibition of GOAT is an effective treatment method of alcohol dependence [non-patent document 11], stimulant dependence or narcotic dependence [non-patent document 12].
It has been reported that ghrelin and a receptor thereof are expressed in proliferative tumors such as prostate cancer and breast cancer [non-patent document 13]. An antitumor effect may be exhibited by controlling ghrelin in charge of cell proliferation signals.
Accordingly, a compound having a GOAT inhibitory activity is extremely useful for the prophylaxis or treatment of metabolic diseases (e.g., obesity, metabolic syndrome, diabetes etc.); the treatment of cardiovascular diseases (e.g., hypertension [non-patent document 14], cardiac failure etc.); and the treatment of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease etc.), ischemic cerebral dysfunctions (e.g., cerebrovascular dementia, cerebral apoplexy, cerebral infarction etc.), alcohol/stimulant dependence, narcotic dependence, proliferative tumors including′ prostate cancer and breast cancer.
WO 2008/001931 (patent document 1) has reported, as a GPR40 agonist, the following compound
R1 is R6—SO2— (wherein R6 is a substituent) or an optionally substituted 1,1-dioxidotetrahydrothiopyranyl group;X is a bond or a divalent hydrocarbon group;R2 and R3 are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydroxy group;R4 and R5 are the same or different and each is a C1-6 alkyl group optionally substituted by hydroxy group(s);ring A is a benzene ring optionally further having substituent(s) selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an optionally substituted amino group; ring B is a 5- to 7-membered ring;Y is a bond or CH2; andR is an optionally substituted hydroxy group.
WO 2010/143733 (patent document 2) has reported, as a GPR40 agonist, the following compound
whereinR1 is a halogen atom, hydroxy, optionally substituted C1-6 alkyl or optionally substituted C1-6 alkoxy,R2 is optionally substituted hydroxy,R3 is a hydrogen atom, a halogen atom or optionally substituted C1-6 alkyl,X is CH2 wherein R1 and X in combination optionally form a optionally substituted ring,Y is CH2, NH or O,Z is CH or N,n is an integer selected from 1 to 3, andA is a halogen atom, optionally substituted amino, or a 4- to 13-membered cyclic group optionally substituted by 1 to 5 substituents selected from(1) a halogen atom,(2) optionally substituted amino,(3) optionally substituted C1-6 alkylthio,(4) optionally substituted C1-6 alkyl,(5) optionally substituted C3-10 cycloalkyl,(6) optionally substituted C1-6 alkoxy,(7) optionally substituted C6-14 aryl,(8) optionally substituted 4- to 7-membered heterocyclic group, and(9) optionally substituted 4- to 7-membered heterocyclyloxy.
WO 2009/137500 (patent document 3) has reported, as a hepatitis C polymerase inhibitor, the following compound
whereinR1 is hydrogen, halogen, cyano or alkyl;R2 is halogen, optionally substituted alkyl, optionally substituted alkoxy or the like;R3 is —NR10SO2R11, —NRwCOORz, —NRxRy, (particular substituent)-ring, or the like;R4 is hydrogen, halogen, cyano, alkyl or the like;R5 is alkyl, cycloalkyl or the like;R6 is optionally substituted aryl;R10 is H, —SO2-alkyl or the like;R11 is optionally substituted alkyl or the like;Rw is hydrogen, alkyl or the like;Rz is alkyl or the like; andRx and Ry are each independently optionally substituted alkyl or the like.
WO 00/69844 (patent document 4) has reported, as a PDEIV inhibitor, the following compound
whereinA and D in combination form phenyl, pyridyl, pyrimidinyl or the like, wherein the ring is optionally substituted by —OR5;R5 is C1-15 alkyl optionally substituted by OH, C1-6 alkoxy, phenyl or the like;E is O or S;R1 is hydrogen, C1-4 alkyl or the like;R2 and R3 are each independently hydrogen, C3-6 cycloalkyl or the like; andR4 is optionally substituted C6-10 aryl, or optionally substituted 5- to 7-membered heterocycle which is optionally fused with benzene.
WO 95/02402 (patent document 5) has reported as a 5-lipoxygenase inhibitor, the following compound
wherein
R3 is hydrogen, cation, aroyl or C1-12 alkanoyl;B is O or S;R4 is NR5R6 or the like;R5 is hydrogen or C1-6 alkyl;R6 is hydrogen, C1-6 alkyl or the like;W is —O—(CH2)s—;S is 0-1;R1 is (CH2)m—Ar—(X)v, O(CH2)m—Ar—(X)v or S(CH2)m-Ar-(X)v;m is 0-3;v is 1-3;Ar is, phenyl or naphthyl; andX is F.